Impaired migration and delayed differentiation of pancreatic islet cells in mice lacking EGF-receptors

Citation
Pj. Miettinen et al., Impaired migration and delayed differentiation of pancreatic islet cells in mice lacking EGF-receptors, DEVELOPMENT, 127(12), 2000, pp. 2617-2627
Citations number
62
Categorie Soggetti
Cell & Developmental Biology
Journal title
DEVELOPMENT
ISSN journal
09501991 → ACNP
Volume
127
Issue
12
Year of publication
2000
Pages
2617 - 2627
Database
ISI
SICI code
0950-1991(200006)127:12<2617:IMADDO>2.0.ZU;2-O
Abstract
Pancreatic acini and islets are believed to differentiate from common ducta l precursors through a process requiring various growth factors. Epidermal growth factor receptor (EGF-R) is expressed throughout the developing pancr eas. We have analyzed here the pancreatic phenotype of EGFR deficient (-/-) mice, which generally die from epithelial immaturity within the first post natal week. The pancreata appeared macroscopically normal. The most strikin g feature of the EGF-R (-/-) islets was that instead of forming circular cl usters, the islet cells were mainly located in streak-like structures direc tly associated with pancreatic ducts. Based on BrdU-labelling, proliferatio n of the neonatal EGF-R (-/-) beta-cells was significantly reduced (2.6+/-0 .4 versus 5.8+/-0.9%, P<0.01) and the difference persisted even at 7-11 day s of age. Analysis of embryonic pancreata revealed impaired branching morph ogenesis and delayed islet cell differentiation in the EGF-R (-/-) mice. Is let development was analyzed further in organ cultures of E12.5 pancreata, The proportion of insulin-positive cells was significantly lower in the EGF -R (-/-) explants (27+/-6 versus 48+/-8%, P<0.01), indicating delayed diffe rentiation of the beta cells. Branching of the epithelium into ducts was al so impaired. Matrix metalloproteinase (MMP-2 and MMP-9) activity was reduce d 20% in EGF-R (-/-) late-gestation pancreata, as measured by gelatinase as says. Furthermore, the levels of secreted plasminogen activator inhibitor-1 (PAI-1) were markedly higher, while no apparent differences were seen in t he levels of active uPA and tPa between EGF-R (-/-) and wild-type pancreata , Our findings suggest that the perturbation of EGF-R-mediated signalling c an lead to a generalized proliferation defect of the pancreatic epithelia a ssociated with a delay in beta cell development and disturbed migration of the developing islet cells as they differentiate from their precursors. Upr egulated PAI-I production and decreased gelatinolytic activity correlated t o this migration defect. An intact EGF-R pathway appears to be a prerequisi te for normal pancreatic development.